bims-musmir Biomed News
on microRNAs in muscle
Issue of 2025–01–12
eleven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. miRNA-1 regulation is necessary for mechanical overload-induced muscle hypertrophy in male mice.
  2. Loss of TDP-43 Splicing Repression Occurs in Myonuclei of Inclusion Body Myositis Patients.
  3. BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia.
  4. Delineating sex-dependent and anatomic decline of motor functions in the SOD1G93A mouse model of amyotrophic lateral sclerosis.
  5. Pharmacological reduction of lipid hydroperoxides as a potential modulator of sarcopenia.
  6. The RNA-binding protein HuR impairs adipose tissue anabolism in pancreatic cancer cachexia.
  7. Skeletal Muscle Mass Loss Leads to Prolonged Mechanical Ventilation and Higher Tracheotomy Rates in Critically Ill Patients.
  8. Gallic acid alleviates exercise-induced muscle damage by inhibiting mitochondrial oxidative stress and ferroptosis.
  9. Skeletal muscle ribosome analysis: A comparison of common assay methods and utilization of a novel RiboAb antibody cocktail.
  10. Generation of a novel mouse model of nemaline myopathy due to recurrent NEB exon 55 deletion.
  11. Screening the human miRNA interactome reveals coordinated up-regulation in melanoma, adding bidirectional regulation to miRNA networks.
  1. Physiol Rep. 2025 Jan;13(1): e70166
    miRNA-1 regulation is necessary for mechanical overload-induced muscle hypertrophy in male mice.
    Shengyi Fei, Blake D Rule, Joshua S Godwin, C Brooks Mobley, Michael D Roberts, Ferdinand von Walden, Ivan J Vechetti.
      MicroRNAs (miRNAs) are small, noncoding RNAs that play a critical role in regulating gene expression post-transcriptionally. They are involved in various developmental and physiological processes, and their dysregulation is linked to various diseases. Skeletal muscle-specific miRNAs, including miR-1, play a crucial role in the development and maintenance of skeletal muscle. It has been demonstrated that the expression of miR-1 decreases by approximately 50% in response to hypertrophic stimuli, suggesting its potential involvement in muscle hypertrophy. In our study, we hypothesize that reduction of miR-1 levels is necessary for skeletal muscle growth due to its interaction to essential pro-growth genes. Promoting a smaller reduction of miR-1 levels, we observed a blunted hypertrophic response in mice undergoing a murine model of muscle hypertrophy. In addition, our results suggest that miR-1 inhibits the expression of Itm2a, a membrane-related protein, as potential miR-1-related candidate for skeletal muscle hypertrophy. While the exact mechanism in muscle hypertrophy has not been identified, our results suggest that miR-1-regulated membrane proteins are important for skeletal muscle hypertrophy.
    Keywords:  hypertrophy; miR‐1; skeletal muscle
    DOI:  https://doi.org/10.14814/phy2.70166
  2. Ann Neurol. 2025 Jan 06.
    Loss of TDP-43 Splicing Repression Occurs in Myonuclei of Inclusion Body Myositis Patients.
    Chiseko Ikenaga, Andrew B Wilson, Katherine E Irwin, Aswathy Peethambaran Mallika, Collin Kilgore, Irika R Sinha, Elizabeth H Michelle, Jonathan P Ling, Philip C Wong, Thomas E Lloyd.
       OBJECTIVE: Inclusion body myositis (IBM) is an idiopathic inflammatory myopathy with muscle pathology characterized by endomysial inflammation, rimmed vacuoles, and cytoplasmic mislocalization of transactive response DNA-binding protein 43 (TDP-43). We aimed to determine whether loss of TDP-43 splicing repression led to the production of "cryptic peptides" that could be detected in muscle biopsies as a useful biomarker for IBM.
    METHODS: We used an antisera against a neoepitope encoded by a TDP-43-dependent cryptic exon within hepatoma-derived growth factor-like protein 2 (HDGFL2) for immunohistochemical analysis on muscle biopsy samples of 122 patients with IBM, 181 disease controls, and 16 healthy controls without abnormal muscle pathology. In situ hybridization was also utilized to detect the localization of cryptic HDGFL2 transcripts.
    RESULTS: We found cryptic HDGFL2 peptides localized within myonuclei from muscle biopsies in 79 of 122 patients with IBM (65%), and this staining correlated with TDP-43 depletion. In contrast, cryptic HDGFL2 immunoreactivity was absent in 197 muscle biopsies from a variety of disease controls, except for 2 patients with vacuolar myopathies. Notably, we show that cryptic HDGFL2 transcripts are accompanied by the detection of cryptic HDGFL2 in muscle fibers of IBM without rimmed vacuoles and TDP-43 aggregates.
    INTERPRETATION: Together, our findings establish that loss of TDP-43 splicing repression occurs in myonuclei of IBM skeletal muscle and suggest that detection of cryptic peptides in muscle biopsies may be a useful biomarker. We suggest that a therapeutic strategy designed to restore TDP-43 function should be considered to attenuate the degeneration of skeletal muscle in this devastating disease. ANN NEUROL 2025.
    DOI:  https://doi.org/10.1002/ana.27167
  3. Cancers (Basel). 2024 Dec 11. pii: 4133. [Epub ahead of print]16(24):
    BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia.
    Claudia Fornelli, Marc Beltrà, Antonio Zorzano, Paola Costelli, David Sebastian, Fabio Penna.
       BACKGROUND AND AIMS: Cancer cachexia is a complex syndrome affecting most cancer patients and is directly responsible for about 20% of cancer-related deaths. Previous studies showed muscle proteolysis hyper-activation and mitophagy induction in tumor-bearing animals. While basal mitophagy is required for maintaining muscle mass and quality, excessive mitophagy promotes uncontrolled protein degradation, muscle loss and impaired function. BNIP3, a key mitophagy-related protein, is significantly increased in the muscles of both mice and human cancer hosts. This study aimed to define the potential of mitigating mitophagy via BNIP3 downregulation in preserving mitochondrial integrity, counteracting skeletal muscle loss in experimental cancer cachexia.
    METHODS: Two in vivo gene delivery methods were performed to knock down muscle BNIP3: electroporation of a BNIP3-specific shRNA expression vector or adenovirus injection.
    RESULTS: The electroporation effectively reduced muscle BNIP3 in healthy mice but was ineffective in C26 tumor-bearing mice. In contrast, adenovirus-mediated BNIP3 knockdown successfully decreased BNIP3 levels also in tumor hosts. Although BNIP3 knockdown did not impact overall on body or muscle mass, it improved muscle fiber size in C26-bearing miceh2, suggesting partial prevention of muscle atrophy. Mitochondrial respiratory chain complexes (OxPhos) and TOM20 protein levels were consistently rescued, indicating improvements in mitochondrial mass, while H2O2 levels were unchanged among the groups, suggesting that BNIP3 downregulation does not impair the endogenous control of oxidative balance.
    CONCLUSIONS: These findings suggest that a fine balance between mitochondrial disposal and biogenesis is fundamental for preserving muscle homeostasis and highlight a potential role for BNIP3 modulation against cancer-induced muscle wasting.
    Keywords:  BNIP3; cancer cachexia; mitochondria; mitophagy; muscle wasting
    DOI:  https://doi.org/10.3390/cancers16244133
  4. bioRxiv. 2024 Dec 17. pii: 2024.12.17.628968. [Epub ahead of print]
    Delineating sex-dependent and anatomic decline of motor functions in the SOD1G93A mouse model of amyotrophic lateral sclerosis.
    Oksana Shelest, Ian Tindel, Marie Lauzon, Ashley Dawson, Ritchie Ho.
      The transgenic SOD1G93A mouse model is the most widely used animal model of amyotrophic lateral sclerosis (ALS), a fatal disease of motor neuron degeneration. While genetic background influences onset and progression variability of motor dysfunction, the C57BL/6 background most reliably exhibits robust ALS phenotypes; thus, it is the most widely used strain in mechanistic studies. In this model, paresis begins in the hindlimbs and spreads rostrally to the forelimbs. Males experience earlier onset, greater disease severity, and shorter survival than females. However, the influence of sex on patterns of declining motor function between forelimbs and hindlimbs as well as among distinct, spinal-innervated muscle groups within each limb are not fully understood. To provide a higher resolution framework of degenerating motor function across the body, we conducted more comprehensive, limb-dependent and independent measures of motor decline over the course of disease. Subsequently, we compared the timing and intensity of these features across sex, and we consider to what extent these patterns are conserved in clinical observations from human ALS patients. We found male mice experienced earlier and less localized onset than females. We also report distinct motor features decline at different rates between sexes. Finally, mice showed differences in correlation between the decline of left- and right-side measures of the hindlimb. Consequently, our findings reinforce and refine the utility of the SOD1 mouse in modeling more highly resolved, sex-specific differences in ALS patient motor behavior. This may better guide preclinical studies in stratifying patients by sex and anatomical site of onset.
    DOI:  https://doi.org/10.1101/2024.12.17.628968
  5. J Physiol. 2025 Jan 08.
    Pharmacological reduction of lipid hydroperoxides as a potential modulator of sarcopenia.
    Jacob L Brown, Hongyang Xu, Elizabeth Duggan, Craig S Rosenfeld, Holly Van Remmen.
      We previously reported that elevated expression of phospholipid hydroperoxide glutathione peroxidase 4, an enzyme that regulates membrane lipid hydroperoxides, can mitigate sarcopenia in mice. However, it is still unknown whether a pharmacological intervention designed to modulate lipid hydroperoxides might be an effective strategy to reduce sarcopenia in aged mice. Here we asked whether a newly developed compound, CMD-35647 (CMD), can reduce muscle atrophy induced by sciatic nerve transection. We treated mice daily with vehicle or CMD (15 mg/kg, i.p. injection) starting 1 day prior to denervation. CMD treatment reduced hydroperoxide generation and blunted muscle atrophy by over 17% in denervated muscle. To test whether CMD can reduce ageing-induced muscle atrophy and weakness, we treated mice with either vehicle or CMD (15 mg/kg, i.p. injection) 3 days per week for 8 months, starting at 18 months of age until 26 months of age. We measured muscle mass, functional status of neuromuscular junctions, muscle contractile function and mitochondrial function in control and CMD-treated 26-month-old female mice. Treatment with CMD conferred protection against muscle atrophy in both tibialis anterior and extensor digitorum longus that was associated with maintenance of fibre size of MHC 2b and 2x fibres. Mitochondrial respiration was also protected in CMD-treated mice. We also found that muscle force generation was protected with CMD treatment despite denervation in ∼25% of the muscle fibres. Overall, this study shows that pharmacological interventions designed to reduce lipid hydroperoxides might be effective for preventing sarcopenia. KEY POINTS: Sarcopenia in aged mice is associated with muscle loss, contractile dysfunction, denervation, and reduced mitochondrial respiration. CMD-35647 is a pharmocological compound that can neutralize lipid hydroperoxides. 8 month treatment of CMD-35647 mitigated muscle atrophy in tibialis anterior and extensor digitorum longus. 8 month treatment of CMD-35647 improved muscle function in aged mice independent of the neuromuscular junction. Aged mice treated with CMD-35647 had greater respiration in red gastrocnemius muscle when compared to vehicle treated mice.
    Keywords:  Aging; Mitochondria; Neuromuscular junction; lipid hydroperoxide; muscle atrophy; muscle weakness; oxylipin; sarcopenia
    DOI:  https://doi.org/10.1113/JP287090
  6. bioRxiv. 2024 Dec 27. pii: 2024.12.27.630549. [Epub ahead of print]
    The RNA-binding protein HuR impairs adipose tissue anabolism in pancreatic cancer cachexia.
    Paige C Arneson-Wissink, Katherine Pelz, Beth Worley, Heike Mendez, Peter Pham, Grace McCarthy, Alex Chitsazan, Jonathan R Brody, Aaron J Grossberg.
       Background: Cachexia is defined by chronic loss of fat and muscle, is a frequent complication of pancreatic ductal adenocarcinoma (PDAC), and negatively impacts patient outcomes. Nutritional supplementation cannot fully reverse tissue wasting, and the mechanisms underlying this phenotype are unclear. This work aims to define the relative contributions of catabolism and anabolism to adipose wasting in PDAC-bearing mice. Human antigen R (HuR) is an RNA-binding protein recently shown to suppress adipogenesis. We hypothesize that fat wasting results from a loss of adipose anabolism driven by increased HuR activity in adipocytes of PDAC-bearing mice.
    Methods: Adult C57BL/6J mice received orthotopic PDAC cell (Kras G12D ; p53 R172H/+ ; Pdx1-cre) (OT-PDAC) or PBS (sham) injections. Mice exhibiting moderate cachexia (9 days after injection) were fasted for 24h, or fasted 24h and refed 24h before euthanasia. A separate cohort of PDAC mice were treated with an established HuR inhibitor (KH-3, 100 mg/kg) and subjected to the fast/refeed paradigm. We analyzed body mass, gross fat pad mass, and adipose tissue mRNA expression. We quantified lipolytic rate as the normalized quantity of glycerol released from 3T3-L1 adipocytes in vitro, and gonadal fat pads (gWAT) ex vivo.
    Results: 3T3-L1 adipocytes treated with PDAC cell conditioned media (CM) liberated less triglyceride into the culture media than control-treated adipocytes (-28.1%) and had lower expression of lipolysis and lipogenesis genes than control cells. PDAC gWAT cultured ex vivo displayed decreased lipolysis compared to sham gWAT (-54.7%). PDAC and sham mice lost equivalent fat mass after a 24h fast, however, PDAC mice could not restore inguinal fat pads (iWAT) (-40.5%) or gWAT (-31.8%) mass after refeeding. RNAseq revealed 572 differentially expressed genes in gWAT from PDAC compared to sham mice. Downregulated genes (n=126) were associated with adipogenesis (adj p=0.05), and expression of adipogenesis master regulators Pparg and Cebpa were reduced in gWAT from PDAC mice. Immunohistochemistry revealed increased HuR staining in gWAT (+74.9%) and iWAT (+41.2%) from PDAC mice. Inhibiting HuR binding restored lipogenesis in refed animals with a concomitant increase in iWAT mass (+131.7%) and genes regulating adipogenesis (Pparγ, Cebpa, Retn, Adipoq, Fasn).
    Conclusions: Our work highlights deficient adipose anabolism as a driver of wasting in 3T3-L1 adipocytes treated with PDAC conditioned media and OT-PDAC mice. The small molecule KH3, which disrupts HuR binding, was sufficient to restore adipogenic and lipogenic gene expression and prevent adipose wasting. This highlights HuR as a potentially targetable regulatory node for adipose anabolism in cancer cachexia.
    Keywords:  HuR; adipogenesis; adipose; cachexia; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1101/2024.12.27.630549
  7. J Clin Med. 2024 Dec 19. pii: 7772. [Epub ahead of print]13(24):
    Skeletal Muscle Mass Loss Leads to Prolonged Mechanical Ventilation and Higher Tracheotomy Rates in Critically Ill Patients.
    Gabriel M Allgayer, Bernhard Ulm, Andreas P Sauter, Stefan J Schaller, Manfred Blobner, Kristina E Fuest.
      Background: Skeletal muscle mass depletion adversely affects critically ill patient outcomes. Standardized methods for assessing muscle mass in this population are limited, particularly regarding changes during ICU stays and their implications for risk stratification. Methods: In this secondary analysis of our prospective data registry of surgical ICU patients, we used a single slice extracted from a computed tomography scan to determine the patient's direction of absolute change in skeletal muscle mass between two different time points (-14 d to +0 d and +5 d to +21 d) during his or her critical illness. Results: In total, 98 surgical patients were included in the final analysis. A decrease in a patient's skeletal muscle mass is associated with prolonged mechanical ventilation compared to patients whose skeletal muscle mass remained the same or increased (415 vs. 42 h, p = 0.003). Patients losing skeletal muscle mass also needed to be ventilated more frequently (88.3% vs. 60.5%, p = 0.002), had a higher rate of tracheotomy (50.0% vs. 23.7%, p = 0.011), and had an increased ICU length of stay (22 vs. 13 days, p = 0.045). Conclusions: A decreased skeletal muscle index in early critical illness negatively impacts ventilation parameters, highlighting the importance of monitoring and managing muscle mass changes to optimize outcomes in ICU patients.
    Keywords:  artificial respiration; critical illness; intensive care units; mechanical ventilation; skeletal muscle; x-ray computed tomography
    DOI:  https://doi.org/10.3390/jcm13247772
  8. J Transl Med. 2025 Jan 08. 23(1): 30
    Gallic acid alleviates exercise-induced muscle damage by inhibiting mitochondrial oxidative stress and ferroptosis.
    Likai Yu, Di Tian, Zishan Su, Li Zhang, Shaobo Guo, Wenhui Zhu, Yuan Fang, Peimin Wang, Nongshan Zhang.
       BACKGROUND: Skeletal muscle injury caused by excessive exercise is one of the most commonly seen clinical diseases. It is indispensable to explore drugs for treating and relieving skeletal muscle injury. Gallic acid (GA) is a polyphenolic extract that has anti-inflammatory and antioxidant biological activities. However, its function and mechanism in skeletal muscle injury remain unclear.
    METHODS: We first established a skeletal muscle injury model caused by excessive exercise. Histopathological analysis was used to determine the severity of skeletal muscle injury in mice. Techniques such as ELISA, Western blot, and RT-qPCR were used to measure skeletal muscle injury markers including CK, LDH, IL-6, TNF-α, and ferroptosis-related indicators such as Fe2+, MDA, COX2, and GPX4. Transmission electron microscopy was used to observe the morphology of mitochondria. JC-1, DHE, and C11-BODIPY 581/591 probes were used to detect mitochondrial membrane potential, mitochondrial reactive oxygen species (mtROS), and lipid peroxidation levels.
    RESULTS: The results of this study indicate that GA has a positive therapeutic effect on skeletal muscle inflammation and injury induced by excessive exercise. On the one hand, GA can alleviate skeletal muscle mitochondrial injury and redox imbalance by reducing mitochondrial membrane potential level and increasing ATP production. On the other hand, GA can inhibit ferroptosis in skeletal muscle cells induced by excessive exercise through its antioxidant and anti-iron accumulation ability.
    CONCLUSIONS: In summary, GA protects against skeletal muscle injury induced by excessive exercise by inhibiting mitochondrial oxidative stress and ferroptosis pathways, providing new evidence for GA as a promising therapeutic agent for skeletal muscle injury.
    Keywords:  Excessive exercise; Ferroptosis; Gallic acid; Mitochondrial oxidative stress; Skeletal muscle injury
    DOI:  https://doi.org/10.1186/s12967-024-06042-5
  9. Physiol Rep. 2025 Jan;13(1): e70173
    Skeletal muscle ribosome analysis: A comparison of common assay methods and utilization of a novel RiboAb antibody cocktail.
    Joshua S Godwin, J Max Michel, C Brooks Mobley, Gustavo A Nader, Michael D Roberts.
      While total RNA concentrations putatively represent ribosome content, there is a need to homologize various quantification approaches. Thus, total RNA concentrations ([RNA]) provided through UV-Vis spectroscopy (UV), fluorometry-only (Fluor), and fluorometry-based microfluidic chip electrophoresis (MFGE) were examined in C2C12 myotubes and mouse skeletal muscle to determine if values aligned with [18S + 28S rRNA] (i.e., criterion ribosome metric). A novel antibody cocktail (termed RiboAb) was also tested and compared to [18S + 28S rRNA] in these models. In myotubes, 24-h IGF-1 treatments increased [18S + 28S rRNA] (~2.0-fold) and [RNA] based on UV (~1.9-fold), Fluor (~2.3 fold), and MFGE (~2.1-fold). In C57BL/6 mice, 10 days of mechanical overload (MOV) elevated plantaris [18S + 28S rRNA] (~1.7-fold) and [RNA] according to UV (~1.5-fold), Fluor (~1.6-fold), and MFGE (~1.8-fold). Myotube and mouse plantaris RiboAb levels were significantly higher with IGF-1 treatments and MOV, respectively, versus controls (1.3-fold and 1.7-fold, respectively), and values correlated with [18S + 28S rRNA] (r = 0.637 and r = 0.853, respectively, p ≤ 0.005). UV, Fluor, and MFGE [RNA] are seemingly valid surrogates of cell/tissue ribosome content, although each method has advantages (e.g., ease of use) and disadvantages (e.g., magnitudes of bias) discussed herein. Finally, the RiboAb cocktail may also represent ribosome content, although this should be further explored in other models.
    Keywords:  RiboAb; UV–Vis; electrophoresis; fluorometry; ribosome pelleting; total RNA
    DOI:  https://doi.org/10.14814/phy2.70173
  10. Res Sq. 2024 Dec 17. pii: rs.3.rs-5456324. [Epub ahead of print]
    Generation of a novel mouse model of nemaline myopathy due to recurrent NEB exon 55 deletion.
    Zachary Coulson, Justin Kolb, Nesrin Sabha, Esmat Karimi, Zaynab Hourani, Coen Ottenheijm, Henk Granzier, James J Dowling.
      Biallelic pathogenic variants in the nebulin ( NEB ) gene lead to the congenital muscle disease nemaline myopathy. In-frame deletion of exon 55 (ΔExon55) is the most common disease-causing variant in NEB . Previously, a mouse model of Neb ΔExon55 was developed; however, it presented an uncharacteristically severe phenotype with a near complete reduction in Neb transcript expression that is not observed in NEB exon 55 patients. We identified by RNA sequencing that the cause of this unexpectedly severe presentation in mice is the generation of a pseudoexon containing two premature termination codons (and promoting nonsense mediated decay) at the Neb exon 55 deletion site. To prove that this is the cause of the loss of Neb transcript, and to generate a more faithful model of the human disease, we used CRISPR gene editing to remove the pseudoexon sequence and replace it with human intron 54 sequence containing a validated cas9 gRNA protospacer. The resulting "hmz" mice have a significant reduction in pseudoexon formation (93.6% reduction), and a re-introduction of stable Neb transcript expression. This new model has the characteristic features of nemaline myopathy at the physiological, histological, and molecular levels. Importantly, unlike the existing exon 55 deletion mice (which die by age 7 days), it survives beyond the first months and exhibits obvious signs of neuromuscular dysfunction. It thus provides a new, robust model for studying pathomechanisms and developing therapies for NEB related nemaline myopathy.
    DOI:  https://doi.org/10.21203/rs.3.rs-5456324/v1
  11. Sci Adv. 2025 Jan 10. 11(2): eadr0277
    Screening the human miRNA interactome reveals coordinated up-regulation in melanoma, adding bidirectional regulation to miRNA networks.
    Faezeh Jame-Chenarboo, Joseph N Reyes, Nicholas M Twells, Hoi Hei Ng, Dawn Macdonald, Eva Hernando, Lara K Mahal.
      Cellular protein expression is coordinated posttranscriptionally by an intricate regulatory network. The current presumption is that microRNAs (miRNAs) work by repression of functionally related targets within a system. In recent work, up-regulation of protein expression via direct interactions of messenger RNA with miRNA has been found in dividing cells, providing an additional mechanism of regulation. Herein, we demonstrate coordinated up-regulation of functionally coupled proteins by miRNA. We focused on CD98hc, the heavy chain of the amino acid transporter LAT-1, and α-2,3-sialyltransferases ST3GAL1 and ST3GAL2, which are critical for CD98hc stability in melanoma. Profiling miRNA regulation using our high-throughput miRFluR assay, we identified miRNA that up-regulated the expression of both CD98hc and either ST3GAL1 or ST3GAL2. These co-up-regulating miRNAs were enriched in melanoma datasets associated with transformation and progression. Our findings add co-up-regulation by miRNA into miRNA regulatory networks and add a bidirectional twist to the impact miRNAs have on protein regulation and glycosylation.
    DOI:  https://doi.org/10.1126/sciadv.adr0277
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